This invention relates to a process for reacting a chlorophthalic acid with aniline to produce a chloro N-phenylphthalimide. In particular, it relates to such a process wherein the only solvent is water.
3,4,6-Trichloro-N-phenylphthalimide (TiCNPP)is an intermediate used in the preparation of quinolone antibacterial drugs. Until now, this compound was prepared by reacting 3,4,6-trichlorophthalic acid (TiCPA) with aniline in glacial acetic acid. See "An Expedient Route to the Quinolone Antibacterial Intermediate, 3,4,5-Trifluorobenzoic Acid" by Neil J. O'Reilly et al. Synlett Letters, page 609 (1990). While that method successfully produced TiCNPP, it was not entirely satisfactory because it also produced sodium acetate, which created a waste disposal problem. In addition, the process for producing the TiCPA was performed in water (see U.S. Pat. No. 4,981,999) and the use of glacial acetic acid therefore required isolating the TiCPA from the water before reacting it with the aniline.
Since the process for producing the TiCPA was conducted in water and water is inexpensive, it might seem reasonable to attempt the reaction of that starting material with aniline in water as well. However, for several reasons it was widely believed that the reaction would not occur in water. First, the reaction is reversible and one of the products of the reaction is water, so it was thought that the presence of water would shift the reaction equilibrium toward the starting material. Second, the phenyl group provided by the aniline performs only the function of protecting the diacid groups during subsequent fluorination of the chlorine groups with potassium fluoride. After the fluorination is complete, the phenyl group is removed and the diacid is formed once again. Since the phenyl group is not an essential portion of the product, the reaction was attempted with methyl amine, which would provide a methyl group to protect the diacid groups during fluorination. However, when methyl amine was tried in water, even under a variety of reaction conditions, no product was produced. Since methyl amine is more soluble and more reactive than aniline and did not work in water, it was concluded that the reaction of TiCPA with aniline would not occur in water.